This invention relates generally to the topical and transdermal administration of pharmacologically active agents, and more particularly relates to permeation enhancer compositions for enhancing the permeability of skin or mucosal tissue to topically applied pharmacologically active agents.
Skin is a structurally complex, relatively thick membrane. In order to deliver a drug into and through the skin, i.e., xe2x80x9ctransdermally,xe2x80x9d drug molecules must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum that present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low without the use of some means to enhance the permeability of the skin.
In order to increase the rate at which a drug penetrates through the skin, various approaches have been followed, each of which involves the use of either a chemical penetration enhancer or a physical penetration enhancer. Methods for physically enhancing skin permeation include, for example, electrophoretic techniques such as iontophoresis. The use of ultrasound (or xe2x80x9cphonophoresisxe2x80x9d) as a physical penetration enhancer has also been researched. Chemical enhancers are compounds that are administered along with the drug (or in some cases used to pretreat the skin, prior to drug administration) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin. Ideally, such chemical penetration enhancers (or xe2x80x9cpermeation enhancers,xe2x80x9d as the compounds are referred to herein) are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum.
Various compounds for enhancing the permeability of skin are known in the art and described in the pertinent texts and literature. Compounds that have been used to enhance skin permeability include: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol(copyright)) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecyl-cyclazacycloheptan-2-one (available under the trademark Azone(copyright) from Nelson Research and Development Co., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid. Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995) provides an excellent overview of the field and further background information on a number of chemical and physical enhancers.
Although many chemical permeation enhancers are known, there is an ongoing need for enhancers that are highly effective in increasing the rate at which a drug permeates the skin, do not result in skin damage, irritation, sensitization, or the like, and can be used to effect transdermal delivery of even high molecular weight drugs such as peptides, proteins, and nucleic acids. Furthermore, it would be a clear advantage commercially if a single enhancer composition could be used to enhance both hydrophilic and hydrophobic drugs. Currently, the enhancers that are used with hydrophilic drugs are not generally effective with hydrophobic drugs, and, conversely, the enhancers that are used with hydrophobic drugs are not generally effective with hydrophilic drugs. It has now been discovered that a combination enhancer, comprised of both a hydrophilic component and a lipophilic component, wherein the hydrophilic component is a hydroxide-releasing agent, is a highly effective permeation enhancer, provide all of the aforementioned advantages relative to known permeation enhancers, and is equally effective with hydrophilic and lipophilic drugs.
It is thus a primary object of the invention to address the above-described need in the art by providing a novel permeation enhancer composition for enhancing the rate at which an active agent administered to a patient""s body surface permeates into and/or through the body surface.
It is another object of the invention to provide such an enhancer composition, wherein the composition contains a hydroxide-releasing agent and a lipophilic co-enhancer.
It is still another object of the invention to provide such an enhancer composition, wherein the lipophilic co-enhancer comprises a fatty acid ester, a fatty alcohol, a fatty ether, or a derivative and/or combination thereof.
It is yet another object of the invention to provide a pharmaceutical formulation containing a therapeutically effective amount of a pharmacologically active agent and an effective permeation enhancing amount of an enhancer composition of the invention.
It is a further object of the invention to provide a drug delivery system for application to a patient""s body surface, containing a therapeutically effective amount of a pharmacologically active agent and an effective permeation-enhancing amount of an enhancer composition of the invention.
It is still a further object of the invention to provide a method for enhancing the flux of an active agent through a body surface, wherein the method involves administering the agent to a localized region of a human patient""s body surface in combination with an effective permeation enhancing amount of an enhancer composition of the invention.
It is yet a further object of the invention to provide such a method wherein the active agent is intended for local delivery, and drug administration is topical.
It is an additional object of the invention to provide such a method wherein the active agent is intended for systemic delivery, and drug administration is transdermal.
Additional objects, advantages and novel features of the invention will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, then, a permeation enhancer composition is provided that is comprised of a hydroxide-releasing agent and a lipophilic co-enhancer, wherein the weight ratio of the hydroxide-releasing agent to the lipophilic co-enhancer is generally in the range of approximately 1:99 to approximately 99:1, preferably in the range of approximately 1:20 to approximately 20:1, and most preferably in the range of approximately 1:2 to approximately 2:1. The hydroxide-releasing agent is generally selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof, although inorganic hydroxides, i.e., ammonium hydroxide, alkali metal hydroxides, and alkaline earth metal hydroxides, are preferred. The lipophilic co-enhancer has a molecular weight in the range of about 150 to 1000 and an aqueous solubility of less than about 1 wt. %. Preferably, the co-enhancer also has a Hildebrand solubility parameter "sgr" in the range of about 2.5 to about 12, preferably in the range of about 5 to about 10. Preferred co-enhancers have the molecular structure (CH3xe2x80x94Lxe2x80x94X)nR, in which:
n is 1 or 2;
L is alkylene or alkenylene containing 1 to 3 double bonds and from about 6 to about 22 carbon atoms;
X is selected from the group consisting of xe2x80x94COOxe2x80x94, xe2x80x94CH2Oxe2x80x94 and xe2x80x94CH2Oxe2x80x94(CO)xe2x80x94; and
R is selected from the group consisting of H, lower alkyl, and lower alkyl substituted with one or two hydroxyl groups, with the proviso that if R is H, X is necessarily xe2x80x94CH2Oxe2x80x94,
wherein when n is 2, R contains at least two carbon atoms.
Preferred lipophilic co-enhancers are fatty acid esters, particularly lower alkyl esters of a C10-C18 fatty acid, and C10-C18 fatty acid mono- and di-esters of polyols such as propylene glycol and glycerol. Preferably, although not necessarily, the enhancer composition has a pH in the range of approximately 8.0 to approximately 13.0, more preferably in the range of approximately 8.0 to 11.5, and optimally in the range of approximately 8.0 to approximately 11.5.
In another aspect of the invention, a pharmaceutical formulation is provided containing a therapeutically effective amount of a pharmacologically active agent, an effective permeation enhancing amount of a permeation enhancer composition as just described, and a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration. The formulation may be in any form suitable for application to the body surface, and may comprise, for example, a cream, lotion, solution, gel, ointment, paste or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres. The formulation may be directly applied to the body surface or may involve use of a drug delivery device. It is preferred although not essential that water be present in order for the hydroxide-releasing agent to generate hydroxide ions and thus assist in enhancing the flux of the active agent through a patient""s body surface. Thus, a formulation or drug reservoir may be aqueous, i.e., contain water, or may be nonaqueous and used in combination with an occlusive overlayer so that moisture evaporating from the body surface is maintained within the formulation or transdermal system during drug administration.
The amount of the hydroxide-releasing agent in the pharmaceutical formulation is preferably the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.5 wt. % to 4.0 wt. % of the formulation. When the active agent is an acid addition salt of a basic compound, the amount in (a) is the amount required to neutralize the acid addition salt and any other acidic species in the formulation. When the active agent is an acidic drug in the form of a free acid, the amount in (a) is the amount required to neutralize the acidic drug and any other acidic species in the formulation. With basic drugs present in the formulation as a neutral, free base, and with basic salts of acidic drugs, the amount in (a) is simply the amount necessary to neutralize inactive components that are acidic, since such drugs are not, clearly, susceptible to neutralization with base. Preferably, although not necessarily, the pharmaceutical formulation has a pH in the range of approximately 8.0 to approximately 13.0, more preferably in the range of approximately 8.0 to 11.5, and optimally in the range of approximately 8.0 to approximately 11.5.
In a further aspect of the invention, a drug delivery system is provided for the topical or transdermal administration of a drug using the dual enhancer composition of the invention. The system will generally comprise: at least one drug reservoir containing the drug and the enhancer composition in an amount effective to enhance the flux of the drug through the body surface; a means for maintaining the system in drug and enhancer transmitting relationship to the body surface; and a backing layer that serves as the outer surface of the device during use. The backing layer may be occlusive or nonocclusive, although it is preferably occlusive. The drug reservoir may be comprised of a polymeric adhesive, which may serve as the basal surface of the system during use and thus function as the means for maintaining the system in drug and enhancer transmitting relationship to the body surface. The drug reservoir may also be comprised of a hydrogel, or it may be a sealed pouch within a xe2x80x9cpatchxe2x80x9d-type structure wherein the drug and hydroxide-releasing agent are present in the pouch as a liquid or semi-solid formulation.
In an additional aspect of the invention, a method is provided for increasing the rate at which an active agent permeates through the body surface of a patient. The method involves administering the agent to a predetermined area of the patient""s body surface in combination with an effective permeation-enhancing amount of a permeation enhancer composition of the invention. The effective permeation enhancing amount of the enhancer composition is preferably an amount effective to provide a pH at the body surface, i.e., during drug administration, in the range of about 8.0 to 13, preferably about 8.0 to 11.5, most preferably about 8.5 to 11.5. If a skin patch is used, this is the preferred pH at the interface between the basal surface of the patch (i.e., the skin-contacting or mucosa-contacting surface of the patch) and the body surface. The optimal amount (or concentration) of the enhancer composition will, however, depend on the specific hydroxide-releasing agent, i.e., on the strength or weakness of the base, its molecular weight, and other factors as will be appreciated by those of ordinary skill in the art of transdermal drug delivery. This optimal amount may be determined using routine experimentation to ensure that the pH at the body surface is within the aforementioned ranges, i.e., in the range of about 8.0 to 13, preferably about 8.0 to 11.5, most preferably about 8.5 to 11.5. A conventional transdermal drug delivery device or xe2x80x9cpatchxe2x80x9d may be used to administer the active agent, in which case the drug and hydroxide-releasing agent are generally present in a drug reservoir or reservoirs. However, the drug and hydroxide-releasing agent may also be administered to the body surface using a liquid or semisolid formulation. Alternatively, or in addition, the body surface may be pretreated with the enhancer, i.e., prior to transdermal drug administration.